Adeno-associated virus (AAV) vectors have the potential to replace conventional anti-retroviral therapies, or even protect against an initial HIV-1 infection. The potential of AAV vectors arises from two properties: their exceptional safety profile, and their ability to sustain very high levels of transgene expression for years. A self-complementary AAV (scAAV) vector can sustain expression of 100-200 pg/ml of protein inhibitors for more than two years. In contrast, transgene expression from a conventional, single-stranded (ssAAV) vector is more than ten-fold lower. However, scAAV transgenes are necessarily half the size of ssAAV transgenes. This limit precludes expression of full-length antibodies, and instead requires use of non-native antibody-like molecules such as single-chain immunadhesins (scFv-Fc). Moreover, the size limitation of scAAV vectors prevents inclusion of other useful molecules, for example the joining (J) chains essential for IgA multimerization, and proteins and regulatory regions useful in various off-switch strategies. It is therefore important to determine if ssAAV-expressed transgenes can suppress viral replication with efficiencies comparable to those achievable with scAAV vectors. This project will address this issue and then explore the contribution of the Fc regions of IgGI, lgG2, and IgA to suppresion of HIV-1 replication and transmission. Aim 1 of this project seeks to enhance the transgene expression of ssAAV vectors expressing full-length antibodies, and determine if these improved vectors can suppress HIV-1 as effectively as scAAV-expressed transgenes. Aim 2 asks whether antibody effector mechanisms other than neutralization contribute to suppression of HIV- 1 in vivo. Aim 3 compares the usefulness of IgGI, lgG2 and IgA in limiting virus transmission. These studies will help determine which vectors, transgenes, and approaches can best suppress an ongoing HIV-1 infection, or prevent viral transmission.